Despite advances in treatment, patients with heart failure eventually become refractory to conventional therapies. Injection of bone marrow derived cells into the heart has shown promise to improve cardiac function in these patients. However, the mechanisms for this improvement and the optimal cell types for improvement are not known. In this proposal we seek to define the mechanisms by which bone marrow derived stem cells improve cardiac function. We propose a Phase I/II human study in which we will inject autologous bone marrow cell fractions into the hearts of patients undergoing placement of left ventricular assist device as a bridge to cardiac transplantation. At the time of transplant we will identify, excise and process the injected areas for histologic evaluation of cardiac vascularity and fibrosis. The primary hypotheses we will test are: 1. Injection of autologous bone marrow cells into the hearts of patients during left ventricular assist device placement is safe. 2. Bone marrow derived cells transdifferentiate into components of the myocardium. 3. CD34+ stem cells are necessary but not sufficient to increase vascularity and decrease fibrosis in the heart. 4. The fibrogenic potential of cardiac macrophages is altered by injection of autologous bone marrow cells. Testing these hypotheses will give important insights into the mechanisms by which bone marrow stem cells may alter cardiac structure. In addition, these studies will provide a framework for testing other novel therapies in humans with end stage heart disease. PUBLIC HEALTH RELEVANCE: Congestive heart failure is a major cause of morbidity and mortality in America. There are currently few therapies besides cardiac transplantation for end-stage heart failure. These studies will increase understanding of how bone marrow derived cells may be used to treat congestive heart failure.